There is an urgent need for mechanistically distinct new antidepressants as less than 50% of major depressive disorder (MDD) patients achieve full remission. Moreover, despite over 50 years of tremendous efforts, only one or two mechanistically new drug classes have been developed for MDD treatment. Due to a limitation of available techniques, it has been extremely difficult to investigate the function of a selective type of neurons in the complex brain, and to further define potential drug targets. By employing viral-mediated gene transfer and optogenetic approaches, we defined neuronal plasticity, in ventral tegmental area (VTA) dopamine (DA) neurons of the brain reward circuitry, that are both sufficient and necessary to underlie susceptibility and resilience to chronic social defeat, a model of depression. In this model, some mice exposed to chronic social defeat exhibit depression-like behaviors such as social avoidance behavior or lower sucrose intake (anhedonia) (susceptibility to depression), while others are normal (resilience to depression). At the cellular level, chronic defeat increased the in vivo firing rate and bursting events of VTA DA neurons in susceptible mice, but not in the resilient subgroup. In freely-behaving resilient mice, light activation of channelrhodopsin-2 (ChR2) (mimicking bursting events) in VTA DA neurons increased avoidance behavior during social interaction test. To explore potential drug targets in these neurons, we investigated the ionic mechanisms that underlie the higher pathological firing. I found that the current of Ih (hyperpolarization-activated cation channels), an important channel in the VTA that plays a key role in the regulation of burst firing, was increased in susceptible mice, and surprisingly, increased even significantly more in the resilient subgroup. I also found that potassium (K+) channel function was selectively increased only in resilient mice. These data strongly support that Ih channels of VTA DA neurons are one of the passive pathological ion mechanisms that underlie the susceptible phenotype, while K+ channels are an important active ion mechanism that drive the higher firing back to normal levels and provides the ability of resilient mice to successfully cope with stressful conditions and avoid developing depression-like behaviors. We therefore hypothesize, in this translational project, that both passive ion channel blockers or active ion channel activators, that inhibit the higher pathological firing of VTA DA neurons, are antidepressant or pro-resilient. Highly consistent with this hypothesis, I found interesting rapid and long-lasting antidepressant effects of Ih inhibitors, which is very different from standard antidepressants that take weeks to have treatment effects. And more importantly, my data showed that a K+ channel activator tended to reverse avoidance behavior in the same manner as traditional antidepressants. These consistent studies, based on defining VTA DA neurons as cellular targets with viral-mediated gene transfer and optogenetic techniques, provide very promising new drug targets for MDD treatment, which are mechanistically different from traditional monoamine-based antidepressants. PUBLIC HEALTH RELEVANCE: In this translational project, we propose to define mechanistically new drug targets for the treatment of major depressive disorder on the basis of our solid, exciting basic research findings in a well-established model of depression. The proposed research is highly clinically relevant because these studies would ultimately expand the limited field of therapeutics treatments for depression and fully benefit depressed patients. The findings from this project therefore are highly relevant to NIMH's mission.